Midkine-A novel player in cardiovascular diseases

Abstract

Midkine (MK) is a 13-kDa heparin-binding cytokine and growth factor with anti-apoptotic, pro-angiogenic, pro-inflammatory and anti-infective functions, that enable it to partake in a series of physiological and pathophysiological processes. In the past, research revolving around MK has concentrated on its roles in reproduction and development, tissue protection and repair as well as inflammatory and malignant processes. In the recent few years, MK's implication in a wide scope of cardiovascular diseases has been rigorously investigated. Nonetheless, there is still no broadly accepted consensus on whether MK exerts generally detrimental or favorable effects in cardiovascular diseases. The truth probably resides somewhere in-between and depends on the underlying physiological or pathophysiological condition. It is therefore crucial to thoroughly examine and appraise MK's participation in cardiovascular diseases. In this review, we introduce the MK gene and protein, its multiple receptors and signaling pathways along with its expression in the vascular system and its most substantial functions in cardiovascular biology. Further, we recapitulate the current evidence of MK's expression in cardiovascular diseases, addressing the various sources and modes of MK expression. Moreover, we summarize the most significant implications of MK in cardiovascular diseases with particular emphasis on MK's advantageous and injurious functions, highlighting its ample diagnostic and therapeutic potential. Also, we focus on conflicting roles of MK in a number of cardiovascular diseases and try to provide some clarity and guidance to MK's multifaceted roles. In summary, we aim to pave the way for MK-based diagnostics and therapies that could present promising tools in the diagnosis and treatment of cardiovascular diseases.

Keywords: biomarkers; cardiovascular disease; cytokine; inflammation; midkine; therapeutic targets.

Figure 1

Human MK Protein. Schematic illustration of human MK protein, after signal sequence cleavage. MK is compiled by an N-terminal and a C-terminal half, signified by blue boxes. Whereas, the former entails the N-tail (aa 1–14) and N-domain (aa 15–52), the latter is composed by the C-domain (aa 62–104) and C-tail (aa 105–121). The hinge region in white (aa 53–61) connects both domains. The C-domain contains several heparin-binding sites. Figure was adapted from Weckbach et al. (14).

Figure 2

Beneficial MK functions in cardiovascular diseases. MK exercises advantageous and protective functions in some cardiovascular diseases. The mechanisms and signaling pathways utilized by MK are illustrated.

Figure 3

Detrimental MK functions in cardiovascular diseases. MK plays injurious roles in a wide scope of cardiovascular diseases. The various mechanisms and signaling pathways through which MK negatively contributes to the pathogenesis of several cardiovascular diseases are depicted.